The targeted aim of Project 4 is to develop therapies to mitigate late effects of radiation on the hematopoietic system. This robust cellular system is damaged by radiation resulting in life-threatening infections, anemia, and bleeding. While the hematopoietic syndrome is well characterized, much less is known about the longterm effects of sublethal radiation on the bone marrow. Our preliminary studies indicate that external sublethal radiation leads to late cytopenias and striking decreases in hematopoietic stem cells (HSC) numbers and function. These preliminary findings support the hypothesis that sublethal external radiation causes significant late marrow injury particularly to the HSC compartment. A bioterrorist attack or nuclear disaster would lead not only to acute external radiation exposure, but also to internal exposure through inhalation and/or ingestion of radioactive particulates. In collaboration with current U19 investigators, we have determined that low dose internal 137Cs, unlike external radiation, causes unexpectedly severe late effects to hematopoietic progenitors. We hypothesize that internal radiation may cause a distinct, previously unexplored pattern of hematopoietic injury. We also hypothesize that combined external plus internal radiation may cause synergistic hematopoietic damage and lead to marrow failure. In Aims 1 and 2, we will more fully define the late effects of external versus internal versus combined external/internal sublethal irradiation on the stem, progenitor, and peripheral blood cell compartments. A better understanding of the response of the hematopoietic system to irradiation will provide for a rational approach to its mitigation following nuclear accident or attack. The substance P analog, Homspera, has been shown to increase hematopoietic progenitor numbers and protect mice from lethal radiation. In Aim 3, we will test the ability of Homspera, as well as the antioxidant EUK-207, to mitigate the late effects of radiation-induced injury to the hematopoietic system. During ontogeny, the sites of hematopoiesis transition from yolk sac to fetal liver to postnatal bone marrow. In Aim 4, we will test the hypothesis that the hematopoietic system is highly vulnerable to radiation injury as it migrates from liver to marrow in the early post-natal period.